Peroxiredoxins (Prxs) are enzymes that neutralize hydrogen peroxide (H2O2), thereby limiting oxidative stress. PrxI and PrxII are abundant and localized to the cytosol. However, H2O2 also serves as an intracellular signaling molecule. For example, H2O2 produced by NADPH oxidases (Nox) acts to oxidize and inactivate protein tyrosine phosphatases when cells are stimulated with growth factors, such as platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) (see Toledano et al.). Inactivation of Prx enzymes by oxidation of the catalytic Cys residue (a process referred to as hyperoxidation) has been proposed as a way to limit Prx activity to enable H2O2 signaling. However, hyperoxidized PrxI or PrxII has not been detected in PDGF-stimulated cells; therefore, Woo et al. investigated alternate mechanisms of Prx inactivation. In vitro assays revealed that PrxI phosphorylated at Tyr194 (a residue that was also phosphorylated in PrxII) was less active than unphosphorylated PrxI. Phosphorylation of PrxI or PrxII at Tyr194 occurred after stimulation with PDGF or EGF of various cell types, including rat smooth muscle cells, but was reduced in cells deficient in Nox1. RNA interference and pharmacological inhibitors of Src family tyrosine kinases indicated that PrxI phosphorylation was partially mediated by c-Src after stimulation of PDGF receptors (PDGFRs), EGF receptors (EGFRs), or B cell receptors (BCRs) and occurred in a membrane-associated, detergent-resistant fraction where c-Src is also found. Growth factor signaling promotes wound healing, and in a model of cutaneous wound repair, PrxI phosphorylation was higher in the wound edge than in the regenerated area. In cells exposed to both PDGF and H2O2, PrxI was phosphorylated and PrxII was hyperoxidized. Prx hyperoxidation results in oligomerization, a structural change that confers chaperone function, and oligomerization of phosphorylated PrxI was not detected. The authors propose that inactivation of PrxI by phosphorylation occurs near growth factor or immune receptors to enable localized H2O2-mediated signaling and that oligomerization of hyperoxidized PrxII represents a distinct phenomenon that occurs during oxidative stress.